What is Malignant Pleural Effusion?
Malignant pleural effusion (MPE) is a condition where cancerous cells are found in the fluid in the space between the lungs and chest wall, known as the pleural fluid. This typically signifies that the cancer has spread systemically throughout the body, a stage also known as M1a. When doctors talk about the stage of cancer, they use a TNM system: ‘T’ for the size of the tumor and extent of spread into nearby tissue, ’N’ for the spread of cancer into close lymph nodes, and ‘M’ for metastasis, which is the spread of cancer to other parts of the body.
Cancerous cells have been identified from pleural fluid, even in patients without apparent fluid buildup, and this can indicate small, unseen spread of cancer. This is linked with a greater likelihood of the cancer coming back and poorer survival rates. The spread of cancer can directly affect the lining of the lungs and chest wall (known as the pleura), either through the blood or the tumor.
The accumulation of fluid is mainly due to changes in the balance of forces (referred as Starling forces) that control fluid mechanics within the pleural space. This fluid buildup is influenced by the difference between various forces within the lungs and pleural space. Fluid absorption primarily happens through lymphatic vessels that carry excess fluid, but any problem with drainage can lead to fluid buildup due to blockage or other issues.
Types of cancers largely associated with pleural involvement include lung, breast, and blood cancers. About half of patients with these conditions develop effusion, the buildup of fluid. The presence of fluid in the pleural space signifies worse prognosis than if it were dry. Also, the number of effusions in cancer patients has been seen to be exudative (rich in protein and other substances) in up to 77% of cases. The incidences of eosinophilic pleural effusions have seen an increase, this is the condition where there is an unusually high amount of eosinophils (type of white blood cell) in the pleural fluid.
While MPE is one of the causes of effusion in a cancer patient, other causes should also be considered. Malignant pleural effusion should not be confused with paramalignant pleural effusions, which means the fluid accumulation isn’t directly caused by cancer cells in the pleural space. Trapped lung, which is a long lasting non-expanded lung that fails to re-expand and septated pleural effusions, where there are fibrous partitions within the fluid, represent underlying causes that need to be addressed.
Worldwide, 70 out of every 100,000 people are affected by MPE. In the U.S. in 2016, MPE accounted for over 361,000 hospital admissions and cost approximately $10.1 billion, leading to substantial impact on the healthcare system. Symptoms such as breathlessness, pain, weight loss, fatigue, and reduced daily activities significantly affect the patient’s quality of life. The prognosis is often poor, with survival ranging between 3 to 12 months.
Breathlessness is the most common symptom linked with pleural involvement. The main aim of treatment is to reduce these symptoms while ensuring a good quality of life and cost-effectiveness of treatment. There are many different therapeutic options, and recently there has been a move towards focusing on outcomes that matter to the patient, rather than the success of specific procedures. Increasing research is being done to understand the role of various cells and growth factors, and how the immune system responds in the pathogenesis of this condition. Novel treatments involve targeted immunotherapies, understanding the role of specific immune cells in curing this condition.
What Causes Malignant Pleural Effusion?
The development of MPE (a condition where there is excess fluid in the space between the lungs and chest wall) can be caused by various factors. Understanding these factors can help guide treatment decisions.
Anatomical Factors
The pleural space is the area that lies between the envelope-like layers that cover the lungs – the parietal and visceral pleurae. The parietal pleura lines the inside wall of the chest while the visceral pleura closely covers the lung tissue. These two layers meet at a point called the hilum. The layer-to-layer connection and maintained negative pressure within the pleural space ensure that these layers don’t separate. Additionally, the normal fluid present in the pleural space aids the movement of one layer over the other.
On average, the pleural space contains around 10 milliliters of fluid per 0.13 (0.26 +/- 0.1) milliliters per kilogram of body weight. This fluid balance can be upset by factors like direct invasion by tumor cells, hormone imbalance, disruptions to the physical structure, or external factors like limited lung movement, blockage of small openings in the pleura (pleural stomata), and mechanical compression. These factors impair the function of the pleural lymphatics, reducing the reabsorption of the fluid. This can result in excess fluid buildup in the pleural space.
Physiological Factors
Increased production of fluid in the pleural space and decreased reabsorption can cause the development of MPE. This imbalance is often initiated by tumor cells due to modifications in gene expression that can lead to changes in blood flow within the pleural space.
Molecular Factors
Various chemical signals can cause the blood vessels in the pleural space to become leaky, leading to an overproduction of pleural fluid. These signals include inflammatory substances like interleukin 2, tumor necrosis factor, and interferon; molecules promoting the formation of new blood vessels like angiopoietin 1 and 2; and other substances like vascular endothelial growth factor, chemokine (C-C motif ligand), matrix metalloproteinases, and osteopontin that have been directly linked to increased blood vessel leakiness.
Genetic Factors
Mutations in certain genes like KRAS, EGFR, MET, BRAF, PIK3CA, and RET are associated with the development of MPE. With advancements in genetic sequencing techniques, identifying these genes could lead to targeted therapies in the future.
Impact on Breathing
The buildup of fluid in the pleural space has been linked to a decrease in the oxygen levels in the blood. As well, a mild abnormal connection within the lungs can lead to reduced oxygen supply to the arteries. Relief from breathlessness following successful removal of the pleural fluid (thoracentesis) brings to attention the impact of fluid buildup on breathing dynamics.
The accumulation of pleural fluid, alterations in breathing movements, coughing, and changes in lung volume activate certain receptors, which is believed to be the underlying cause of breathing difficulty in MPE. Changes in the movement of the diaphragm and shifts in pressure-volume relationships due to increased chest volume and pressure from the fluid accumulation can also contribute to breathlessness. Changes in the relationship between muscle length and tension have also been shown to cause difficulty in breathing.
Risk Factors and Frequency for Malignant Pleural Effusion
Malignant pleural effusion (MPE) is a health condition caused by cancer cells in the pleura, which leads to fluid buildup between the lung and the chest wall. This complication is common in patients with cancer, with around 500,000 new cases seen each year in both the United States and Europe. MPE can be present in around 20% of cancer patients and can be associated with any type of cancer.
- MPE commonly indicates severe cancer. On average, patient survival is between 3 to 12 months from the time of diagnosis.
- MPE is seen in 90% of lung cancer cases, usually indicating the direct invasion of the pleura by small cell carcinoma cells.
- Approximately 2% to 11% of breast cancer patients develop MPE, often due to spread through the pleural lymphatics. This condition is commonly tied with the more severe triple-negative breast cancer.
- MPE in patients with ovarian cancer usually indicates a slightly better prognosis compared to other cancers.
- Almost 25% of cases can have bilateral involvement, and MPE frequently occurs in both Hodgkin and non-Hodgkin Lymphoma.
- In patients with Hodgkin Lymphoma, MPE can be present at the time of diagnosis in about 20% of the cases. However, in around 60% of the patients, it signifies progression of the disease.
- In cases associated with malignant mesothelioma, MPE is seen in about 50% to 94% of the patients and indicates that the tumor might not respond to the standard chemotherapy treatment.
- Bilateral pleural effusions are seen in 15% of those who are non-critically ill and 55% of the critically ill population.
Signs and Symptoms of Malignant Pleural Effusion
A brief health history and understanding of a patient’s other health conditions help identify the causes of Malignant Pleural Effusion (MPE). This information also helps health professionals understand a patient’s ability to handle certain treatments.
How MPE affects patients can depend on the amount and speed of fluid build-up in the chest and the patient’s general health. Common MPE symptoms include shortness of breath, pain, cough, and clubbing or thickening of the fingers and toes.
Shortness of breath, also known as dyspnea, is the most common symptom seen in MPE, while mechanical factors and pre-existing conditions like lung collapse, pulmonary arterial hypertension, and ventilation-perfusion mismatch can contribute to it.
Pain in the chest can indicate chest wall involvement or malignant pleural mesothelioma. People with these conditions may experience increased pain when taking deep breaths, a condition known as pleuritic chest pain. However, pain can also present as a dull ache rather than the typical sharp, stabbing sensation associated with pleuritis.
Coughing, especially when it produces blood-tinged mucus, can signify inflammation of the pleura or bronchi. Other symptoms that suggest advanced underlying disease include loss of appetite, weight loss, fatigue, and lethargy.
- Shortness of breath
- Pain (may increase with deep breaths)
- Coughing (may be productive and contain traces of blood)
- Loss of appetite
- Weight loss
- Fatigue
- Lethargy
Clubbing, a condition characterized by the thickening of the fingers and toes, can be validated through physical indications such as the Lovibond and Schamroth signs and a depth ratio between the nail bed and interphalangeal fold greater than 1.
Patients may also display symptoms related to paraneoplastic manifestations, such as muscle weakness, seizures, confusion, increased urination, and signs related to Cushing syndrome. Other effects of the condition may include headache, voice alteration, confusion, facial and brachial swelling, and symptoms of Horner syndrome.
Compounding these symptoms, an occupational history of asbestos exposure may be of note, as asbestos is often linked to mesothelioma and lung cancer. A family history of malignancy can be a clue to the underlying cause of MPE. A review of medication history, particularly drugs like amiodarone, nitrofurantoin, and methotrexate, is also important as these are known to cause fluid build-up in the chest.
The physical examination complements the patient’s history and aims to identify the source of the symptoms. The general physical examination, chest inspection, percussion, and auscultation are of particular focus. Examination findings can help guide the choice of treatment and management approaches. For instance, diminished or absent breath sounds and pleuritic rub indicate pleural effusion. Special techniques such as egophony, which distinguishes changes in vocal timber, and whispering pectoriloquy, which is the clear hearing of whispered sound via a stethoscope, can also offer valuable indicators.
In summary, key physical examination findings include dullness to percussion and decreased vocal vibrations. These signs suggest the likely presence of pleural effusion, although confirmation should be through a chest radiograph. In the absence of reduced vibration on examination, a chest radiograph may not be necessary unless there is a high degree of clinical suspicion. Fluid needs to have accumulated in a significant quantity to present noticeable changes in a physical examination. Signs such as rapid breathing, significantly reduced chest expansion, absent or noticeably reduced vocal vibrations and breath sounds, bulging of spaces between the ribs, and specific changes in voice and breath sounds suggest an accumulation of more than 1500 mL of fluid.
Testing for Malignant Pleural Effusion
When doctors suspect a person has a malignant pleural effusion (MPE), a condition where there’s abnormal accumulation of fluid in the chest, they use a mix of imaging and tissue testing to confirm the diagnosis.
Imaging techniques are essential for detecting pleural fluid (fluid around the lungs), evaluating the spread of the condition, locating any related tumors, guiding any necessary fluid draining, and monitoring how well treatments are working.
A simple chest X-ray is commonly the first tool used to evaluate symptoms of pleural effusion. For an X-ray to show pleural fluid, there needs to be a certain amount present (at least 200 mL of fluid). An X-ray can also show certain changes in the chest structure that suggest a diagnosis, such as crowding of the ribs or uplift of the diaphragm. Sometimes, the scan may show a large accumulation of fluid which can indicate a more serious underlying condition.
Thoracic ultrasound, another type of imaging, is more sensitive than an X-ray, meaning it can spot smaller amounts of fluid. It can also help doctors identify features like blood within the pleural space or areas where fluid has collected and guide procedures accurately.
CT scans are considered the best tool for identifying underlying pleural diseases, revealing details such as the extent of pleural thickening (a sign of a possible malignancy) and other changes. A special scoring system, using multiple factors, could also help doctors distinguish between malignant and benign conditions.
A type of imaging called positron emission tomography can help visualize mixed lesions and target specific areas of the pleura to look for signs of disease.
Magnetic resonance imaging (MRI) provides excellent soft tissue detail, making it better than CT scans for detecting involvement of the chest wall and diaphragm in the disease. However, due to high costs and other limitations, MRI is typically not included in routine diagnostic tests.
A key part of diagnosing MPE is histopathological diagnosis, or studying the cells and tissues under a microscope. This provides detailed information about the cells and their architecture, crucial for identifying malignant cells. Tests such as fluid cytology, cell block preparation, and pleural biopsy significantly improve detection of MPE and guide treatment strategies.
One common method used to investigate MPE is diagnostic thoracentesis, a procedure that collects pleural fluid samples. Pleural fluid analysis helps distinguish benign from malignant disease through various parameters, including pH level, protein content and white blood cell count. Additionally, protein markers in the fluid can be detected in cases of MPE.
A biopsy of pleural tissue is recommended for patients with negative cytology results. This procedure involves removing a small piece of tissue from the chest cavity for microscopic examination. Advanced techniques including image-guided biopsies and thoracoscopy, which involves looking at the inside of the chest using a thin tube with a light and camera, can increase the accuracy of diagnosis.
Lastly, pleural manometry is a technique where doctors measure the pressure within the pleural space, the thin gap between two layers that cover the lungs. This can help with diagnosing an unexpandable lung following thoracentesis – a condition where the lung can’t fully inflate – although the specific pressure limits to identify a normal lung and an unexpanded lung still need to be agreed upon.
Treatment Options for Malignant Pleural Effusion
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What else can Malignant Pleural Effusion be?
If you are experiencing issues with your lungs or chest, the doctor will typically consider various conditions that could be creating these symptoms. These conditions could fall under different areas, which are usually:
Clinical differential diagnoses: Diseases with similar symptoms could include:
- Liver enlargement
- Pleural thickening (a condition that can develop after having tuberculosis or empyema)
- Elevated hemidiaphragm (possibly due to a paralyzed phrenic nerve)
- Plaques
- Lung consolidation (when the air in your lungs is replaced with another substance)
- Lobar collapse (when part of your lung does not inflate properly)
Radiological differential diagnoses: Diseases identified through imaging tests could include:
- Pleural thickening
- Pseudo-plaques (which are plaque-like lung opacities formed by small nodules situated right next to the lung’s outer layer or visceral pleura and are common in sarcoidosis, coal workers’ pneumoconiosis, and silicosis)
- Benign and malignant plaques
- Inferior pulmonary ligament
Doctors might also need to differentiate between different types of fluid accumulation around the lungs including Paramalignant pleural effusion and MPE due to their distinct implications. Other such conditions include congestive heart failure, hepatic decompensation, and renal failure. Certain treatments like radiotherapy, conventional chemotherapy, targeted therapy, and immunotherapy could also cause these accumulation issues.
Lastly, certain conditions could show negative results on cytology, a diagnostic technique, but still manifest issues. They may include nonspecific pleuritis that can arise from radiation and chemotherapy-induced inflammation of the pleura (the membrane that surrounds your lungs). Regular checks are important for such patients due to the potential risk of diagnosing a pleural malignancy later on.
What to expect with Malignant Pleural Effusion
The LENT, modified LENT, and PROMISE scores are different methods used to predict the outcomes related to malignant pleural effusion (MPE). These methods may have limitations because they may not include some newer targeted treatments for MPE.
The LENT score uses measures like the amount of LDH protein in your pleural fluid (the fluid between the layers of tissue lining your lungs and chest wall), your health status according to the Eastern Cooperative Oncology Group, the ratio of two types of white blood cells, and the type of tumor you have. The PROMISE score uses a wider range of health indicators, including the levels of different proteins in your body, to forecast your chances of survival after 3 months and whether a specific treatment called pleurodesis will be successful.
The SELECT score, another tool, predicts 90-day survival using factors like your sex, health status, white blood cell count, status of a specific protein (epidermal growth factor receptor), whether you’re undergoing chemotherapy, and the type of the primary tumor. The SELECT score has been found to provide better predictions of survival compared to LENT and PROMISE scores. The modified LENT gives comparable results to the SELECT score in predicting survival.
However, predicting outcomes could also be tailored to the individual by using information like patient preferences, specific therapy options, side-effects burden and adopting newer treatments. Predicting outcomes in advanced diseases may use tools like the PPI which comprises of a health performance scale, swelling, difficulty breathing, reduced food intake, and confusion. A PPI score above 4.5 usually indicates less than 6 weeks survival. Moreover, it’s recommended to use treatments like chest tube drainage, chemical sealing of the lungs (pleurodesis), and talc drainage guided by a minimally invasive procedure called thoracoscopy, rather than repeating certain procedures due to risks involved.
In lung cancer patients with MPE, having a specific type of genetic change (actionable mutation) presents a similar risk of recurrence, as not having any actionable mutation. In a research, it was found that larger pleural effusion size, higher pleural fluid LDH, and positive fluid examination results were linked to higher chances of fluid accumulation in the chest.
Possible Complications When Diagnosed with Malignant Pleural Effusion
Possible complications from Malignant Pleural Effusion (MPE) include “trapped lung”, ongoing air leaks after a tube is inserted in the chest (for instance if you have a puncture in the lung), and an effusion with dividing sections. Procedures used to drain fluid from around the lungs can lead to some complications too. These procedures include spreading a talc-like substance inside the chest through a small camera (thoracoscopic talc poudrage), injecting the talc substance directly (talc slurry), inserting a permanent tube (tunneled catheter insertion), and fusing the layers around the lung to prevent fluid buildup (pleurodesis). It’s important to note that MPE can’t be cured – the main goal of treatment is to relieve symptoms. We should also keep in mind the financial burdens on families who are already handling the costs of cancer treatment, as they might need repeated procedures.
Side Effects and Complications:
- Trapped lung
- Persistent air leaks after tube insertion
- Septated effusion
- Complications from procedures like thoracoscopic talc poudrage, talc slurry, and pleurodesis
- Financial challenges from repeated procedures
Preventing Malignant Pleural Effusion
The American Thoracic Society, a leading organization for lung health, has created a comprehensive guide for patients to understand the use of in-dwelling catheters in treating Malignant Pleural Effusion (MPE). MPE is a condition where there is abnormal collection of fluid in the space between the lungs and the chest cavity.
The guide explains why these catheters are used, the potential risks associated with their use, as well as how to care for them and the eventual removal process. Catheters are flexible tubes inserted into the body to provide or drain fluids. It’s important that patients regularly meet with healthcare experts for check-ups after a catheter has been placed for MPE. This routine follow-up helps in monitoring the patient’s condition and ensuring the catheter is working properly.
